Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

Cancer Discov. 2018 May;8(5):582-599. doi: 10.1158/2159-8290.CD-16-0861. Epub 2018 Mar 6.

Abstract

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Computational Biology / methods
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • N-Myc Proto-Oncogene Protein / genetics*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neoplasm Staging
  • Neuroblastoma / diagnosis
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism*
  • Nuclear Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • RNA Interference
  • Regulatory Sequences, Nucleic Acid*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MYCN protein, human
  • Muscle Proteins
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • TAZ protein, human
  • TEAD4 protein, human
  • Transcription Factors
  • YY1AP1 protein, human
  • Proteasome Endopeptidase Complex